Regenerating Optic Axons Restore Topography after Incomplete Optic Nerve Injury SARAH A. DUNLOP, 1,2 * LISA B.G. TEE, 1 MICHEL A.L. GOOSSENS, 1 R. VICTORIA STIRLING, 1 LIVIA HOOL, 3 JENNY RODGER, 1,2 AND L.D. BEAZLEY 1,2 1 School of Animal Biology, University of Western Australia, Crawley, 6009, Australia 2 Western Australian Institute for Medical Research, University of Western Australia, Crawley, 6009, Australia 3 School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, 6009, Australia ABSTRACT Following complete optic nerve injury in a lizard, Ctenophorus ornatus, retinal ganglion cell (RGC) axons regenerate but fail to restore retinotectal topography unless animals are trained on a visual task (Beazley et al. [1997] J Comp Neurol 370:105–120, [2003] J Neuro- trauma 20:1263–1270). Here we show that incomplete injury, which leaves some RGC axons intact, restores normal topography. Strict RGC axon topography allowed us to preserve RGC axons on one side of the nerve (projecting to medial tectum) while lesioning those on the other side (projecting to lateral tectum). Topography and response properties for both RGC axon populations were assessed electrophysiologically. The majority of intact RGC axons retained appropriate topography in medial tectum and had normal, consistently brisk, reliable re- sponses. Regenerate RGC axons fell into two classes: those that projected topographically to lateral tectum with responses that tended to habituate and those that lacked topography, responded weakly, and habituated rapidly. Axon tracing by localized retinal application of carbocyanine dyes supported the electrophysiological data. RGC soma counts were normal in both intact and axotomized RGC populations, contrasting with the 30% RGC loss after complete injury. Unlike incomplete optic nerve injury in mammals, where RGC axon regen- eration fails and secondary cell death removes many intact RGC somata, lizards experience a “win–win” situation: intact RGC axons favorably influence the functional outcome for regenerating ones and RGCs do not succumb to either primary or secondary cell death. J. Comp. Neurol. 505:46 –57, 2007. © 2007 Wiley-Liss, Inc. Indexing terms: optic nerve regeneration; incomplete optic nerve transection; visual projections; topography; electrophysiological mapping; axonal tracing; reptiles A long-term goal of comparative neuroscience research is to suggest ways to induce functional central nerve re- generation in mammals, including human. One example of the potential of such an approach is that studies com- paring optic nerve regeneration in fish and mammals have informed strategies to induce axon regeneration in mam- mals (Bastmeyer et al., 1993; Blaugrund et al., 1993; Herdegen et al., 1993; Petrausch et al., 2000; Li et al., 2003). However, if function is to be restored, a further crucial aspect of central nerve regeneration must be con- sidered. Many central projections are topographically or- ganized and restoration of such ordered connectivity will be essential for functional repair (Kandel et al., 2000). The relative simplicity of the primary visual system has pro- vided an excellent model to examine factors necessary for the restoration of topography after CNS injury (Meyer, 1998; Beazley, 2000a,b; Schmidt, 2004; Dunlop, 2006). Comparative studies have shown that in anamniotes such as fish, newt, and frog, retinal ganglion cell (RGC) axons regenerate and restore topography within the tec- Grant sponsor: National Health & Medical Research Council (Australia); Grant numbers: 992319, 303226; Grant sponsor: Neurotrauma Research Program (WA); Grant sponsor: NH&MRC; Grant number: 254670 (Senior Research Fellowship to S.A.D.). Current address for L.B.G. Tee: School of Pharmacy, Curtin University of Technology, Bentley, Australia. *Correspondence to: Prof. Sarah A. Dunlop, School of Animal Biology, University of Western Australia, Crawley, 6907, Australia. E-mail: sarah@cyllene.uwa.edu.au Received 13 March 2007; Revised 21 June 2007; Accepted 13 July 2007 DOI 10.1002/cne.21477 Published online in Wiley InterScience (www.interscience.wiley.com). THE JOURNAL OF COMPARATIVE NEUROLOGY 505:46 –57 (2007) © 2007 WILEY-LISS, INC.